Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by mineralization of elastic fibers in skin, arteries and the retina, that result in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency, cardiovascular disease and retinal hemorrhages leading to macular degeneration.
The skin manifestations are among the most common characteristics of PXE, but the ocular and cardiovascular symptoms are responsible for the morbidity of the disease. Characteristic skin lesions are generally an early sign of PXE and were first described by a French dermatologist in 1896. Skin lesions are usually detected during childhood or adolescence and progress slowly and often unpredictably. Therefore, the initial diagnosis of PXE is sometimes made by a dermatologist. The skin lesions consist of yellowish papules and plaques and laxity with loss of elasticity, and result from an accumulation of abnormal mineralized elastic fibers in the mid-dermis. Lesions are typically seen on the face, neck, axilla, antecubital fossa, popliteal fossa, groin and periumbilical areas. A PXE diagnosis can be confirmed by a skin biopsy that shows calcification of fragmented elastic fibers in the mid- and lower dermis.
Another characteristic of PXE is the presence of ocular lesions due to the accumulation of abnormal elastic fibers in the Bruch's membrane, resulting in angioid streaks. Doyne was the first to describe these ocular streaks in 1889, and Knapp introduced the term “angioid streaks” for their resemblance to blood vessels. The combination of PXE and ocular manifestations was initially referred to as the Gronblad-Strandberg syndrome, after the names of two ophthalmologists who independently related the occurrence of angioid streaks to PXE in 1929. The majority of PXE patients (approximately 85%) develop ocular manifestations during their second decade of life. Bilateral angioid streaks are normally seen as linear gray or dark red lines with irregular serrated edges lying beneath normal retinal blood vessels and represent breaks in the Bruch's membrane. The Bruch's membrane is not in a true sense a “membrane” but rather a heterogeneous elastin-rich layer separating the chorioid from the retina. The elastic laminae of the Bruch's membrane is located between two layers of collagen (type I, III and IV) which lie in direct contact with the basement membranes of the retinal pigmented epithelium (RPE) and the capillaries in the choriocapillary layer of the chorioid As a consequence of angioid streaks, a PXE patient progressively develops a chorioidal neovascularization with a subsequent hemorrhagic detachment of the fovea and later scarring. Optic nerve drusen may also be associated with angioid streaks and results in visual field deficits and even advanced visual impairment.
Common cardiovascular complications of PXE are due to the presence of abnormal calcified elastic fibers in the internal elastic lamina of medium-sized arteries. The broad spectrum of phenotypes includes premature atherosclerotic changes, intimal fibroplasia causing angina or intermittent claudication or both, early myocardial infarction and hypertension Fibrous thickening of the endocardium and atrioventricular valves can also result in restrictive cardiomyopathy. Approximately 10% of PXE patients also develop gastrointestinal bleedings and central nervous system complications (such as stroke and dementia) as a consequence of systemic arterial wall mineralization. In addition, renovascular hypertension and atrial septal aneurysm can be seen in PXE patients.
Strikingly, lung abnormalities are not a significant phenotypic feature of PXE, even though pulmonary tissues are rich in elastic fibers. Mineralization of pulmonary elastic fibers has only been noted in a few patients.
PXE is usually found as a sporadic disorder but examples of both autosomal recessive and autosomal dominant forms of PXE have been reported. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Recent reports have linked both the dominant and recessive forms of PXE to a 5 cM domain on chromosome 16P13.1 However, the mechanisms underlying the physiological defects characteristic of PXE are not understood.
Therefore, there is a need in the art for methods and compositions for diagnosing and treating PXE and PXE associated phenotypes.